1,4 - dihydro-1-substituted alkyl-6,7-methylenedioxy - 4 - oxoquinoline-3-carboxylic acid



United States Patent 1,4 DlHYDRO-l-SUBSTITUTED ALKYL-6,7-METH- YLENEDIOXY 4 OXOQUINOLINE-S-CARBOX- YLIC ACID Daniel Kaminsky, Parsippauy, and Robert I. Meltzer,

Rockaway, N.J., assignors to Warner-Lambert Pharmaceutical Company, Morris Plains, NJ., 2 corporation of Delaware No Drawing. Filed May 18, 1967, Ser. No. 639,304

Int. Cl. C07d 33/56 US. Cl. 260-287 Claims ABSTRACT OF THE DISCLOSURE The present invention relates to compositions of matter containing quinolines of the formula:

(1? 04 UjTman N wherein R represents alkyl, substituted lower alkyl, cycloalkyl, alkenyl and aralkyl; R represents O-alkyl, O-mono or dialkylaminoalkyl, O-cycloalkyl, NH-alkyl, NH-aryl,

NHCOOR NHOR, or any readily hydrolyzable group. These compounds are useful as anti-microbial agents.

The present invention relates to anti-bacterial compositions containing as active ingredients, 1,4-dihydro-1-R-6,7- methylenedioxy-4-ox-o-3-quinoline carboxylic acid derivatives of the formula:

mono or dialkylaminoalkyl, NH-lower alkyl, NH-aralkyl, NH-aryl,

where n is 1 to 4, NHCOOR in which R is lower alkyl or aralkyl and R is lower alkyl or R and R taken together with the nitrogen atom may constitute a cyclic moiety such as morpholino, piperidino, or piperazino, etc., and R may also be any readily hydrolyzable group, such as a thioester nitrile, or the like.

In the above definitions of R, R R and R alkyl is meant to include those alkyl groups containing 1 to 12 carbon atoms in a straight or branch chain such as methyl, ethyl, propyl, isopropyl, and the like; cycloalkyl is meant to include from 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclohexyl, and the like; aralkyl is meant to include both monohomocyclic ring systems, such as 'benzyl, as well as heteroaromatic ring systems such as pyridyl, furyl, and the like. The definitions R, R R and 3,524,858 Patented Aug. 18, 1970 R as used hereinafter are to be considered to have the meanings defined above.

The compositions of this invention exhibit potent antibacterial activity particularly against gram negative bacteria, such as the Escherichia group and the Proteus group. Accordingly, they are useful as anti-bacterial agents in the treatment of mammals, such as dogs, guinea pigs, cats, monkeys, and the like, which are infected with bacteria susceptible to these agents. In order to use these compounds, they are combined with known pharmaceutical carriers, such as lactose, starch, dicalcium phosphates, syrup, and the like, to yield various dosage forms such as tablets, suspensions and the like, with the active ingredient being present in amounts of from about to 500 mg. per dosage unit. They may also be combined with sten'le vehicles, such as sterile water, or sterile isotonic saline to form dosage forms suitable for parental administration.

These dosage forms may be compounded according to standard pharmaceutical art. Generally, a dosage regimen of about 100 mg. to 1500* mg, preferably about 250 mg., 3 or 4 times daily, orally or by injection are recommended to treat bacterial infections caused by these gram-negative bacteria. A surprising property of these compositions resides in the discovery that they are more slowly metabolized in the mammalian body and consequently, they are longer acting when compared with other quinoline compounds such as those disclosed in U.S. Pat. No. 3,287,- 458. Because of this prolonged activity, the dosage that is necessary to be administered to a host may be considerably reduced.

The compounds of this invention may also be administered in admixture with animal foodstuffs, for example, they may be mixed from 1 to 25% by weight with foodstuffs such as corn meal, water, and the like.

The compounds of this invention may also be used in a form suitable for topical application. Such compositions may comprise from about 1 to 20% by weight of the selected active ingredient and such standard pharmaceutical diluents which are commonly used in the manufacture of topical compositions, such as talc, Vaseline, or other hydrophobic or hydrophilic ointment bases, and the like. These compositions are applied to infected sites.

The compositions of this invention may also include other known anti-bacterials, such as the tetracyclines, the nitrofurans, the sulfa drugs, and the like to enhance their anti-bacterial spectrum.

The active ingredients of this invention are prepared by four different methods. In the first method (referred to as Method A in the examples below) a compound of the formula:

0 0 Q WC 0 Cl CH2 W a Ra In the third method, (referred to as Method C in the examples) compound II is treated with hydroxylamine or substituted hydroxylamines to yield compounds wherein R is NHOH or NHO R.

In the fourth method (referred to as Method D in the examples) compound II is treated with a carbamate ester (such as ethyl carbamate) to yield compounds wherein R is NHCOOR. Starting compound II is obtained by treating quinolines of the formula:

O u 4 lo 0 o n C 2 i ,1

R (III) with thionyl chloride, oxalyl chloride or other agents generally used to convert acids to acid chlorides. Compound IH is described and disclosed in US. Pat. 3,287,458.

The following examples are included in order further to illustrate the invention.

METHOD A Example 1 1 ethyl 1,4 dihydro-4-oxo-6,7-methylenedioxyquinoline-3-carbonyl chloride.-Thionyl chloride (13.2 g., 0.11 mole) was added to a slurry of 26.1 g. (0.1 mole) of pure l-ethyl-l,4-dihydro-4-oxo-6,7 methylenedioxy-3-quinoline carboxylic acid in 100 ml. dry benzene and the mixture was refluxed for 12 hr. Petroleum ether (250 ml.) was added and the mixture filtered to yield 29 g. of 1-ethyl-1,4 dihydro 4-oxo-6,7-methylenedioxy quinoline 3 carbonyl chloride as yellow brown solid, M.P. 235-236 (dec.). The crude solid was refiuxed with 500 ml. of CH CI and filtered hot to yield 24.3 g. (87%) of light brown solid, 1-ethyl-1,4-dihydro-4-oxo-6,7-methylenedioxy quinoline 3 carbonyl chloride, M.P. 245 (dec.).

Analysis.Calcd. for C H ClNO (percent): C, 55.83; H, 3.60; N, 5.01; CI, 12.68. Found (percent): C, 56.03; H, 3.87; N, 4.94; Cl, 12.87.

Example 2 Cyclohexyl 1-ethyl-1,4 dihydro 4 oxo-6,7-methylenedioxy-quinoline-3-carboxylate.A mixture of 14 g. (0.05 mole) of l-ethyl-1,4-dihydro-4-oxo-6,7 methylenedioxy-quinoline-3-carbonyl chloride. 6 g. (0.06 mole) of freshly distilled cyclohexanol and 30 g. of pyridine was heated for 2 hr. on a steam bath. The volatiles were removed in vacuo and the residue was triturated several times with water and filtered. The crude product was recrystallized from 3:1 CCLpCellosolve B yielding 15.4 g. (90%) of cyclohexyl l-ethyl-1,4-dihydro-6,7-methylenedioxy 4 oxo 3 quinoline-carboxylate, M.P. 204-206".

Analysis.Calcd. for C H NO (percent): C, 66.46; H, 6.16; N, 4.08. Found (percent): C, 66.46; H, 6.24; N, 3.91.

Example 3 Following the procedure of Example 2 and employing analogous reaction conditions, but using ethanol, instead of cyclohexanol, there was obtained ethyl 1-ethy1-1,4- dihydro-6,7-methylenedioxy-4 oxo 3 quinolinecarboxylate, M.P. 177-178".

Analysis.Calcd, for C -H NO (percent): C, 62.28; H, 5.23; N, 4.48. Found (percent): C, 61.99; H, 5.07; N, 4.71.

Example 4 Following the procedure of Example 2 and employing analogous reaction conditions, but using n-propanol instead of cyclohexanol, there was obtained propyl 1- ethyl-1,4 dihydro 6,7 methylenedioxy 4 oxo-3- quinolinecarboxylate, M.P. 158-160.

4 Analysis.Calcd. for C16H1'1NO5 (percent): C, 63.36; H, 5.56; N, 4.62. Found (percent): C, 63.13; H, 5.72; N, 4.74.

Example 5 Following the procedure of Example 2 and employing analogous reaction conditions, but using n-butanol instead of cyclohexanol, there was obtained butyl l-ethyl- 1,4 dihydro 6,7 methylenedioxy 4 oxo-3-quinoline carboxylate, M.P. 131-133.

Analysis.--Calcd. for C H NO (percent): C, 64.35; H, 6.04; N, 4.41. Found (percent): C, 64.23; H, 5.94; N, 4.23.

Example 6 Following the procedure of Example 2 and employing analogous reaction conditions, but using t-amyl alcohol instead of cyclohexanol, there was obtained tert-amyl 1-ethyl-1,4 dihydro 6,7 methylenedioxy 4-oxo-3- quinolinecarboxylate, M.P. 172-173.

Analysis.-Calcd. for C H NO (percent): C, 65.24; H, 6.39; N, 4.23. Found (percent): C, 65.16; H, 6.36; N, 4.46.

Example 7 Following the procedure of Example 2 and employing analogous reaction conditions, but using n-hexyl alcohol instead of cyclohexanol, there was obtained hexyl l-ethyl- 1,4 dihydro 6,7-methylenedioxy-4-oxo-3-quinolinecarboxylate, M.P. -92".

Analysis.--Calcd. for C H NO (percent): C, 66.07; H, 6.71; 'N, 4.06. Found (percent): C, 65.90; H, 6.81; N, 419.

Example 8 Following the procedure of Example 2 and employing analogous reaction conditions, but using n-decyl alcohol instead of cyclohexanol, there was obtained decyl 1- ethyl 1,4-dihydro-6,7-methylenedioxy-4-oxo-3-quinolinecarboxylate, M.P. 99-101".

Analysis.-Calcd. for C H NO (percent): C, 68.80; H,- 7.78; N, 3.49. Found (percent): C, 69.07; H, 7.89; N, 3.70.

Example 9 Following the procedure of Example 2 and employing analogous reaction conditions, but using diethylaminoethanol, instead of cyclohexanol, there was obtained 2- (diethylamino)ethyl 1 ethyl 1,4-dihydro-6,7-methylenedioxy-4-oxo-3-quinolinecarboxylate, M.P. 108-109".

Ana-lysis.-Calcd. for C H N O (percent): C, 63.32; H, 6.71; N, 7.77. Found (percent): C, 63.52; H, 6.75 N, 7.48.

Example 10 The acid chloride obtained by treatment of 1,4-dihydro- 1 methyl 6,7 methylenedioxy 4-oxo-3-quinolinecarboxylic acid with thionyl chloride as in Method A, Example 1, was treated, without isolation, with ethanol to yield ethyl 1,4 dihydro 1-methyl-6,7-methylenedioxy-4- oxo-3-quinolinecarboxylate, M.P. 202-203".

Analysis.Calcd. for C H NO (percent): C, 61.09; H, 4.76; N, 5.09. Found (percent): C, 61.26; H, 4.99; N, 5.08.

Example 11 The acid chloride obtained by treatment of 1-butyl-1,4- dihydro-6,7-methylenedioxy-4-oxo-3-quinoline carboxylic acid with thionyl chloride, as in Method A, Example 1, was treated, without isolation, with ethanol to yield ethyl 1 butyl 1,4 dihydro-6,7-methylenedioxy-4-oxo-3-quinoline carboxylate, M.P. 117-119".

Analysis.-Calcd. for C H NO (percent: C, 64.35; H, 6.04; N, 4.41. Found (percent): C, 64.51; H, 6.23; N, 4.50.

METHOD B Example 1 N (2 diethylaminoethyl)-l-ethyl-1,4-dihydro-4-oxo- 6,7-methylenedioxy-quinoline-3-carboxamide.A mixture of 8.4 g. (0.03 mole) of l-ethyl-1,4-dihydro-4-oxo-6,7- methylenedioxy quinoline-3-car-bonyl chloride, 4.6 g. (0.04 mole) of N,N-diethyl ethylenediamine and 150 ml. of benzene was refluxed for 8 hr. The volatiles were removed under aspirator vacuum and the residue was triturated with 5% NaOH solution and recrystallized from aqueous isopropyl alcohol yielding 10.2 g. (94%), M.P. 192-195 of N (2 diethylaminoethyl) 1-etl1y1-1,4-dihydro 6,7 methylenedioxy 4-oxo-3-quinoline carboxamide, M.P. 199-201.

A nalysis.Calcd. for C H N (percent): C, 63.49; H, 7.01; N, 11.69. Found (percent): C, 63.57; H, 7.05; N, 11.76.

Example 2 Following the procedure of Method C, Example 1, and using m-anisidine there was obtained 1-ethyl-1,4-dihydro- N (m methoxyphenyl) 6,7-methylenedioxy-4-oxo3- quinoline carboxamide, M.P. 240-241 Analysis.-Calcd. for C H N 0 (percent): C, 65.56; H, 4.95; N, 7.65. Found (percent): C, 65.50; H, 5.02; 'N, 7.41.

METHOD C 1-ethyl-1,4-dihydro-4-oxo-6,7-methylenedioxyquinoline- 3-hydroxamic acid.Hydroxylamine hydrochloride (2.1 g., 0.03 mole) was added to a mixture of 4.2 g. (0.015 mole) of l-ethyl-1,4-dihydro-4-oxo-6,7-methylenedioxyquinoline-3-carbonyl chloride in 25 m1. of pyridine. After stirring for 2 hr., the mixture was heated for 3 hr. on a steam bath. The pyridine was removed under aspirator vacuum and the residue was recrystallized from 90% aqueous ethanol to yield 4.0 g. of light yellow crystals (96%) of 1-ethyl-1,4-dihydro-6,7-methylenedioxy-4-oxo- S-quinoline hydroxamic acid, M.P. 265-268. The analytical sample from 95% ethanol had M.P. 269270.

Analysis.-Calcd. for C H N O (percent): C, 56.52; H, 4.38; N, 10.14. Found (percent): C, 56.77; H, 4.47; N, 10.10.

METHOD D Ethyl[ (1 ethyl-1,4-dihydro-4-oxo-6,7-methylenedioxyquinoline 3 yl)carbonyl]carbamates.-A mixture of 8.4 g. (0.03 mole) of l-ethyl-1,4-dihydro-4-oxo-6,7-methylenedioxyquinoline-3-carbonyl chloride, 5.3 g. of (0.06 mole) of ethyl carbamate and 100 ml. of pyridine was refluxed for 8 hr. The solvent was removed in vacuo and the residue triturated with water and recrystallized from 0 0 3 C-R1 a I l wherein R is lower alkyl, hydroxy-lower alkyl, carboxylower alkyl, lower alkenyl, or cycloalkyl, in which cycloalkyl has from 3 to 8 carbon atoms; R is NHOH, NHCOOR NH-Q-ORz, and OCHzCHzN\ in which R is lower alkyl.

2. The compound of claim 1 wherein R is C H and R is NHOH.

3. The compound of claim 1 wherein R is C l-I and R1 iS 4. The compound of claim 1 wherein R is C H and R1 is OCHB 5. The compound of claim 1 wherein R is C H and R1 is OCH2CH2N(C2H5)2.

References Cited UNITED STATES PATENTS 2,614,121 10/1952 Price et al 260--287 X 3,172,811 3/1965 Kaminsky et al. 260287 X 3,287,458 ll/1966 Kaminsky et al 260-287 3,290,315 12/ 1966 Watson 260-287 3,397,208 8/ 1968 Berman 260-287 DONALD G. DAUS, Primary Examiner US. Cl. X.R. 

